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Carbon-11: Radiochemistry and Target-Based PET Molecular Imaging Applications in Oncology, Cardiology, and Neurology

  • Nerella Sridhar Goud*
    Nerella Sridhar Goud
    Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
    *Email: [email protected]
  • Ahana Bhattacharya
    Ahana Bhattacharya
    Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
  • Raman Kumar Joshi
    Raman Kumar Joshi
    Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
  • Chandana Nagaraj
    Chandana Nagaraj
    Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
  • Rose Dawn Bharath
    Rose Dawn Bharath
    Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
  • , and 
  • Pardeep Kumar
    Pardeep Kumar
    Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
Cite this: J. Med. Chem. 2021, 64, 3, 1223–1259
Publication Date (Web):January 26, 2021
https://doi.org/10.1021/acs.jmedchem.0c01053
Copyright © 2021 American Chemical Society
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Abstract

The positron emission tomography (PET) molecular imaging technique has gained its universal value as a remarkable tool for medical diagnosis and biomedical research. Carbon-11 is one of the promising radiotracers that can report target-specific information related to its pharmacology and physiology to understand the disease status. Currently, many of the available carbon-11 (t1/2 = 20.4 min) PET radiotracers are heterocyclic derivatives that have been synthesized using carbon-11 inserted different functional groups obtained from primary and secondary carbon-11 precursors. A spectrum of carbon-11 PET radiotracers has been developed against many of the upregulated and emerging targets for the diagnosis, prognosis, prediction, and therapy in the fields of oncology, cardiology, and neurology. This review focuses on the carbon-11 radiochemistry and various target-specific PET molecular imaging agents used in tumor, heart, brain, and neuroinflammatory disease imaging along with its associated pathology.

1. Introduction

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Positron emission tomography (PET) is regarded as an important molecular imaging modality to study the pathophysiological conditions in animals (preclinical studies), human subjects (clinical studies), and drug development (drug discovery).(1,2) The PET modality plays a wide role in medical diagnosis, mainly in tumors, the heart, and the nervous system. The major advantage of PET is to measure the very low concentration (10–6–10–9 g) of radiotracers at a specific region of interest in a living subject, either animal or human, or throughout a whole body.(3,4) In general, positron-emitting radiotracers like fluorine-18 and carbon-11 are injected intravenously into a specific region of interest, and the tracers generate two γ-rays with 511 keV energy in almost opposite directions after annihilating with an electron in the living subjects.(5) The high-resolution images are obtained from PET detectors based on the distribution of the positron-emitter after reconstruction of coincident arrivals of the γ-rays.(6) The essential steps which are followed in the process of PET imaging include the production of radionuclide, radiolabeling studies with a precursor, imaging, and quantitative analysis.
The limited anatomic data provided by PET scanners is the main drawback. However, this limitation has been largely overcome by multimodality devices like PET-CT, SPECT-CT, and, most recently, PET-MRI. PET scanners are routinely combined with CT and MRI for attenuation correction and anatomical orientation. PET has a high spectral resolution (2–6 mm) [it is higher than that of CT and MRI (≪1 mm)], and the sensitivity of PET (10–12 M) is much greater than the MRI modality (10–4 M). Therefore, PET remains an invaluable molecular imaging modality, even through the combination of PET-CT or PET-MR in biomedical and clinical practice.(7,8)
The imaging output from PET gives clear information related to the distribution of radioactivity and pharmacokinetics which in turn depend on the chemical nature of the radiotracer and the physiological conditions of the living subjects. Thus, the design of a specific radiotracer is an essential step for target selectivity and its distribution in the region of interest. For instance, few of the designed radiotracers are utilized for various purposes; i.e., [18F]FDG (18F-2-fluoro-2-deoxy-d-glucose) (1) shows a report on glucose metabolism which is normal in healthy subjects but shows the high rate in different pathophysiological conditions, such as tumors and various neurological disorders,(9) and [18F]FLT (18F-3′-fluoro-3′-deoxythymidine) (2) is a thymidine kinase-1-based substrate and widely used for the study of cell growth in tumors (Figure 1).(10)[11C]Flumazenil (3) is considered as a ligand for brain GABAA benzodiazepine receptors to study the condition of epilepsy.(11)[11C]Raclopride (4) is a specific D2 and D3 receptor antagonist widely used for the diagnosis of Parkinson’s disease.(12)[11C]Methionine (5) is an aliphatic amino acid involved in amino acid transport and protein incorporation and is widely used in the diagnosis of multiple cancer types.(13)[11C]Choline (6) is the precursor to acetylcholine neurotransmitter synthesis, the activity of which is impaired in a majority of neurodegenerative diseases, and also used in the diagnosis of prostate cancer.(14) The modern computational modeling studies like ligand-based and structure-based drug design and structural–activity relationship studies help identify target-specific drugs.(15)

Figure 1

Figure 1. Commonly used PET radiotracers for diagnosis under various clinical conditions.

1.1. Carbon-11 Radiochemistry

Carbon-11 (t1/2 = 20.4 min, β+ emission = 99.8%) is the most useful short-lived positron-emitting radiotracer for developing PET molecular images. The cyclotron generated carbon-11 radionuclide replaces a stable carbon-12 atom in the desired organic molecule to produce target-based carbon-11 radiotracers.(16) In general, the medical cyclotron generates carbon-11 radionuclide in two different sources, either [11C]carbon dioxide or [11C]methane, using different target material composition through the 14N(p,α)11C nuclear reaction (Figure 2). The [11C]carbon dioxide is produced from nitrogen with oxygen ∼0.1–1% target in high activities around ∼118 GBq with an energy utilization of 11–17 MeV, whereas the [11C]methane is produced from nitrogen with hydrogen ∼10% target in normal activities around ∼67 GBq with an energy utilization of 18 MeV.(17) The [11C]methane production was also reported from cyclotron-produced [11C]carbon dioxide by online reduction with hydrogen and nickel at around 580 °C.(18) The carbon-11 radionuclide undergoes a β+-decay process by losing a positron and an electron neutrino into a stable boron-11 isotope. The method of carbon-11 production is known as the no-carrier-added (NCA) method, which means the theoretical specific (GBq/mg) or molar activity (GBq/μmol) (absence of other than the specified isotope) should be attained. This method is different from the carrier-added (CA) method in which molecular 18F-fluorine (18F–F) is produced, where the theoretical specific (GBq/mg) or molar activity (GBq/μmol) (presence of other including the specified isotope) is not attained. Therefore, the ratio of radioactive to non-radioactive species in NCA (higher molar activities) is always greater than CA (lower molar activities).(19) The PET studies usually need to be NCA for targeting low-density proteins like neurotransmitter receptors, transporters, or plaque to avoid the target protein saturation point with the carrier (non-radioactive molecule) and to reduce the target-based PET signal.(20) Molar activities always depend on time and decay of the radioisotope. Hence, the molar activity values pertaining to a specific time, such as time of radiotracer injection into a PET study subject (TOI), end of radiosynthesis (EOS), and end of radionuclide production (ERP), are also referred to as the end of bombardment (EOB).(21)

Figure 2

Figure 2. Cyclotron production and β+-decay process of carbon-11 radionuclide.

The PET studies in human subjects require about 15 mCi or 550 MBq of carbon-11 radiotracer at the TOI after passing all necessary quality control tests, whereas the PET studies in animal subjects require lower radioactive doses and are based on animal size.(22) Dynamic PET imaging studies require higher NCA molar activities than static PET imaging studies. The majority of PET studies are performed with a NCA radiotracer molar activity value >35 GBq/μmol in human subjects. As the half-life of carbon-11 is 20 min, each step needs to be performed very rapidly, including radiochemical synthesis, purification, final formulation, and dispensing for intravenous injection to a living subject. High-performance liquid chromatography (HPLC) provides the carbon-11 radiotracer purification through specific preparative methods and also determines the radiochemical purity, radiochemical identity, radiochemical yields, and molar activity concentration through analytical methods using suitable chromatographic conditions.(23) Thin-layer chromatography (TLC) provides retardation factor (Rf) values for the carbon-11 radiotracer based on its affinity toward the mobile phase on the silica gel stationary phase and determines the radiochemical purity and radiochemical yield.(24) The gas chromatography (GC) provides residual solvent limits of the final formulation after the radiochemical synthesis in ppm units.(25) The bacterial endotoxin test with limulus amebocyte lysate (LAL) reagent should be passed before injecting into a living subject.(26)
Fluorine-18 mainly follows two methods majorly for radiolabeling like electrophilic radiofluorination and nucleophilic radiofluorination, whereas the carbon-11 follows versatile routes by generating primary and secondary precursors. [11C]Carbonylation is one of the most common approaches for inserting carbon-11 into various drug molecules. The investigation of new carbon-11-based radiosynthesis with direct radioactive materials rather than optimization trials with unlabeled material, unlike fluorine-18, is the major advantage of carbon-11. Carbon-11-based synthons can be generated for opening additional routes for carbon-11 radiolabeling in various selective molecules. The short half-life of carbon-11 is the major limitation, and the proximity of the radiochemist is required to speed up the process.(27,28)

1.2. Carbon-11 Precursors for Radiolabeling

The carbon-11 precursors are classified into primary and secondary based on their utility and wide range of applications in the radiolabeling of various compounds like aliphatic, aromatic, and heterocyclic compounds after the production of carbon-11 radionuclide (Figure 3). It is known that the carbon-11 is generated from cyclotron using the 14N(p,α)11C nuclear reaction through the collision of nitrogen gas with a trace amount of either hydrogen or oxygen. Besides, the nitrogen-13 is also produced in trace amount as an impurity via 16O(p,α)13N nuclear reaction. In practice, the yields of carbon-11 are very high due to a high nitrogen concentration and low oxygen (<1%) levels in the target gas.(29)

Figure 3

Figure 3. Transformation of different precursors from carbon-11 radionuclide.

1.2.1. Primary Carbon-11 Precursors

The carbon-11 in the chemical form of [11C]CO2 and [11C]CH4 is considered as the primary carbon-11 precursors, which can be produced during in-target production. Other primary precursors like [11C]CO and NH4[11C]CN can be generated in the target by changing the l of hydrogen and oxygen along with beam current, but the respective yields are very poor. Even the approaches of developing [11C]CH3I as primary precursors are under scientific validation.(29) The [11C]carbon dioxide has direct utility in the labeling of some compounds, mainly in direct [11C]carboxylation reactions with organometallic reagents, and reactions with amines, etc. The previous reports suggest the direct incorporation of [11C]carbon dioxide (11C–CO2 fixation) into functional groups such as urea ([11C]AR-AO14418, selective GSK-3β inhibitor) (7), carbamate ([11C]GR103545, kappa opioid agonist) (8), oxazolidinone ([11C]SL25.1188, monoamine oxidase-B inhibitor) (9), carboxylic acid ([11C]bexarotene, retinoid X receptor (RXR) agonist) (10), amide (11C-WAY-100635, 5-HT1A receptor agonist) (11), and amine ([11C]PHNO, dopamine D2 and D3 receptor agonist) (12) for the synthesis of various carbon-11 radiotracers (Figure 4).(30−33)

Figure 4

Figure 4. Reaction pathways for [11C]CO2 fixation into urea, carbamates, oxazolidinones, carboxylic acids, amides, and their carbon-11 radiotracer derivatives.

1.2.2. Secondary Carbon-11 Precursors

The primary carbon-11 precursors like [11C]CO2 and [11C]CH4 are converted into secondary precursors by rapid and efficient online or one-pot synthetic procedures to produce building blockers for generating carbon-11 radiotracers. There are several useful transformations for the generation of secondary precursors. Many of the potential radiotracers are generated using various secondary precursors, which include [11C]flumazenil (GABAA benzodiazepine receptors) (3) from 11CH3I precursor, [11C]raclopride (cerebral D2/D3 receptor antagonist) (4) from 11CO precursor, 11C(carbonyl)-estramustine phosphate (estrogen receptor agonist) (13) from 11COCl precursor, [11C]thymidine (pyrimidine derivative for DNA synthesis) (14) from 11COCl2 precursor, [11C]citalopram (selective serotonin reuptake inhibitor) (15) from 11CN precursor, [11C]serine (synaptic N-methyl-d-aspartate receptors) (16) from 11CH2O precursor, [11C]tanaproget (selective progesterone receptor modulator) (17) from 11CS2 precursor, and [11C]NS14492 (α7-subtype nicotinic Ach receptor agonist) (18) from 11CH3OTf precursor (Figure 5).

Figure 5

Figure 5. Reaction pathways for generation of secondary precursors and their carbon-11 radiotracer derivatives.

1.2.2.1. Transformations of Secondary Precursors from [11C]CO2
The 11C-carbon monoxide is an important and widely used secondary labeling agent, which is prepared by reducing [11C]carbon dioxide over heat at 400 °C with zinc or heating at 850 °C with molybdenum. The synthesis of [11C]carbon monoxide was also reported from in situ generated 11C-formate or [11C]formyl chloride from 11C-carbon dioxide with lithium triethylborohydride, hexachloroacetone, and triphenylphosphine; recently, the silyl reagents are used most commonly for generating [11C]carbon monoxide in the liquid phase.(34−36) [11C]Carbon dioxide can also be converted into [11C]formaldehyde by reducing it to [11C]methanol, followed by oxidation over heated silver wool at 350 °C; another method was also reported, i.e., [11C]methyl iodide using trimethylamine N-oxide (TMAO) at 70 °C.(37) [11C]Acyl chloride or aryl acid chloride can be synthesized from [11C]carbon dioxide using an appropriate Grignard reagent followed by subsequent chlorination using either thionyl chloride or phthaloyl dichloride.(38,39) [11C]Methyl iodide is another commonly used secondary agent. A common method of generating [11C]methyl iodide is the reduction of [11C]carbon dioxide with lithium aluminum hydride (LAH) followed by subsequent iodination by hydroiodic acid treatment; another method has been reported through gas-phase iodination of [11C]methane for [11C]methyl iodide synthesis.(40,41) [11C]Nitromethane is synthesized from [11C]methyl iodide by passing over heated silver nitrite at 80 °C,(42) and [11C]methyl isocyanate is generated from [11C]methyl iodide by passing over heated silver cyanate at 180 °C.(43) The [11C]methyl triflate is also generated from [11C]methyl iodide by passing over heated silver triflate at 200 °C,(44) and [11C]methyl iodide can be converted into [11C]carbon disulfide by passing over sulfur through a column and sand at 500 °C.(45)
1.2.2.2. Transformations of Secondary Precursors from [11C]CH4
[11C]Hydrogen cyanide can be synthesized from [11C]methane by passing ammonia over heated platinum at 1000 °C.(46) [11C]Methane is transformed into [11C]fluoroform by passing through helium over heated cobalt(III) fluoride at 270 °C.(47) [11C]Phosgene is synthesized from [11C]carbon tetrachloride, which is generated from [11C]methane by passing over copper(II) chloride on pumice stone at 380 °C, followed by a passage with trace oxygen over heated iron at 300 °C or a passage of [11C]carbon tetrachloride over oxygen in a quartz tube at 750 °C.(48,49)

1.3. Carbon-11 Radiolabeling Strategies

The radiochemistry of carbon-11 is challenging because of the shorter t1/2 of carbon-11 which restricts different synthetic methods and time-consuming processes to use. In addition to its normal optimization reaction procedures, three essential steps are needed to be considered to follow an effective strategy for carbon-11-based radio synthesis.(50)
  • Design reaction protocols to introduce carbon-11 radionuclide at the last step.

  • In order to achieve good radiochemical yields and molar activity, the reaction time should be reduced.

  • Reduce isotopic dilution to achieve maximum molar activities.

With the above aspects of effective strategies for carbon-11-based radiosynthesis, various synthetic methodologies and innovations in technology have been adopted. The organic synthetic methods provide great opportunities for the synthesis of various carbon-11 radiotracers by holding carbon chemistry literature. Many carbon-11 tracers are available based on the simplest methylation of heteroatoms with [11C]methyl iodide,(51) but labeling position may not always be possible in different compounds. Therefore, a large number of methodologies have come into the radiochemical synthesis of carbon-11 through the formation of C–C bonds between carbon-11 and labeling molecules.(52) Currently, the following methods are utilized for the synthesis of various 11C-radiotracers through C–C bond formation.
  • The alkylation of carbanions (nucleophiles) with carbon-11-labeled alkyl halides, nitroalkanes, and cyanide (electrophilic carbon-11).(53)

  • The carboxylation of organometallic reagents, copper, and other metal-mediated catalysts.(54,55)

  • Transition-metal-mediated (palladium, rhodium, and selenium) chemical reactions with [11C]CH3I and [11C]CO.(56−59)

  • Various carbon-11 radiotracers are synthesized through C–C bond formation using different well-known reaction mechanisms like Stille reaction (Pd2(dba)3/11CH3I) for [11C]A85380 (nicotinic Ach receptor agonist) (19), Negishi coupling reaction (Pd(PPh3)2Cl2/11CH3I) for [11C]MPEP (glutamate receptor subtype 5 receptors) (20), Suzuki cross-coupling reaction (Pd(PPh3)2Cl2/11CO) for N-[11C]phenylacetamide derivative (HIV-1 reverse transcriptase inhibitor) (21), Heck reaction (Pd2(dba)3/11CH3I) for [11C]stilbene derivative (targeting amyloid plaques) (22), Sonogashira reaction (Pd2(dba)3/11CH3I) for N-[11C]estradiol derivative (estrogen receptors agonist) (23), and 11C-cyanide cross-coupling reaction (Pd2(dba)3/11CN) for [11C]cyanide derivative (dopamine D3 receptor antagonist) (24) (Figure 6).

Figure 6

Figure 6. Carbon-11 radiotracers through C–C bond formation from various well-known reaction mechanisms.

1.4. Significance of Carbon-11 Labeling in Different Target-Based Heterocycles

The [11C]nicotine (25) as a nicotinic acetyl cholinergic receptor (nAChR) PET imaging agent has been synthesized via two different methods. The first method follows treatment of nornicotine with highly reactive [11C]methyl triflate under mild conditions in acetone at 45 °C for 5 min. The final radiochemical yield obtained was 60.4%. The second method follows treatment of nornicotine with 11C-methyl iodide in the aprotic polar solvents dimethyl sulfoxide–dimethylformamide (DMSO–DMF) at 115 °C for 5 min to study nicotinic receptors with PET, and the radiochemical yield was >90%.(60,61)The [11C]NS14492 (26) PET radiotracer for imaging human cerebral α7 nicotinic acetylcholine receptors (α7nAChR) has been reported. The radiosynthesis of [11C]NS14492 was achieved by the treatment of its desmethyl precursor with 11CH3OTf in a fully automated system using tetrabutylammonium hydroxide (TBAH) and acetone at 60 °C for 30 min. The achieved radiochemical yield was >98%.(62)The protein kinase C radiotracer (27) has been synthesized through 11C-methylation of the arylamine precursor with [11C]CH3I at room temperature that was achieved by inorganic base potassium carbonate in dimethylformamide for 10 min with ultrasonication, and the radiochemical yield was 25%. Another method was also developed for the radiochemical synthesis of other arylamines using [11C]CH3I in good yields. The same group has reported the conversion of primary arylamines into carbon-11-labeled N-methyl secondary arylamines using lithium nitride (Li3N) in DMF with [11C]CH3I at room temperature for 10 min with ultrasonication.(63)The [11C]vemurafenib (28) is a serine/threonine kinase PET imaging agent for the melanomas mainly in the specific expression of the BRAFV600E mutation. The target compound was radiolabeled with [11C]CO through a palladium-catalyzed carbonylative cross-coupling reaction on the arylamine precursor with triphenylarsine and tris(dibenzylideneacetone) palladium (0) [Pd2(dba)3] in tetrahydrofuran (THF) at 100 °C for 5 min. The achieved radiochemical yield was 21%.(64)The S-[11C]methylated mercaptoimidazole piperazinyl derivatives as PET radiotracers have been reported as 5-HT1A receptor imaging agents. In the radiochemical synthesis, the [11C]methyl group was introduced at the C-2 position of an imidazole ring. Thus, the target radiotracer (29) was synthesized through S-methylation of the imidazole thione precursor with [11C]CH3I using NaOH base in ethanol at 80 °C for 6 min and the radiochemical yield was 20–30%.(65)The carbon-11-labeled dihydrobenzoimidazol derivative for imaging of NR1A/2B subtype selective N-methyl-d-aspartate (NMDA) receptors has been reported. The synthesis of the target radiotracer (30) was obtained by treatment of the o-aryl diamine precursor with [11C]phosgene and triethylamine (TEA) in dichloromethane solvent at room temperature for <1 min, and the radiochemical yield was 30–50%.(66)The [11C]oxazolidin-2-one PET radioligand (31) has been developed for imaging monoamine oxidase-B. The precursor ethanolamine derivative was treated with [11C]phosgene in dichloromethane solvent at 100 °C for 2 min, offering the target radiotracer, and the radiochemical yield was 3.5–7%.(67)The triazole-based monoacylglycerol lipase (MAGL) inhibitors have been reported as PET imaging agents. The triazolyl MAGL radioligand (32) was prepared from the secondary amine precursor through the [11C]carbon dioxide fixation method with BEMP base in phosphoryl chloride at RT for 5–6 min with adequate radiochemical yields of 5–13%.(68)

2. PET Molecular Imaging Applications in Oncology

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2.1. Receptor Tyrosine Kinases (RTKs)

Tyrosine kinase receptors get abnormally activated during tumor progression and, in turn, contribute toward inadvertent signaling processes of all cancer hallmarks.(69,70) Carbon-11 was labeled with ligand 3-piperidinylethoxyanilinoquinazoline (PAQ), which is an analogue to tyrosine kinase inhibitor (TKI) vandetanib having 40 times higher Ki inhibition against VEGFR-2. [11C]PAQ (33) was used as a PET molecular probe in MMTV-PyMT/FVB (PyMT), a transgenic mouse model of breast cancer, to monitor the anticancer treatment in the animal. The study showed promising results indicating the potential of (R)-[11C]PAQ as a predictive radiotracer in cancer therapy response treatment.(71) The RTKs include an extracellular domain as well as intracellular signaling cascades; these are the targets for various monoclonal-antibody-based small-molecule TKIs, respectively.(72) For the in vivo assessment of pharmacokinetics and biodistribution, TKIs could be radiolabeled with carbon-11. A case report published in 2011 explored the target expression of EGFR and the binding potential of erlotinib using [11C]erlotinib (34) (Tarceva) in a patient with metastases.(73) Other TKI-PET tracers like [11C]lapatinib (35) and [11C]osimertinib (36) were used to study the target expression of HER2 (receptor tyrosine-protein kinase erbB-2) and the brain accessibility and biodistribution in human brain tumors.(74,75)

2.2. Phosphatidylcholine (PC)

Phosphatidylcholine, a phospholipid in eukaryotic cell membranes, is overexpressed in tumor cells, providing a potential target for tumor imaging. Elevated levels of PC are due to the enhanced uptake of choline, which is the precursor of PC.(70−76)[11C]Choline ([11C]CHO) (6) can serve as a potential PET imaging marker for imaging cell proliferation, since it is in proliferating cancer cells. [11C]CHO has been studied in several other types of tumors, including prostate cancer,(77) brain tumors,(78) and many other types of tumors. [11C]CHO is used for the analysis and delineation of HGG, LGG, and extra-axial tumors.(79−81) Its dependency on BBB disruption limits its application as a PET tracer.(82) The Giovacchini group performed a [11C]CHO imaging study in hormone-sensitive prostate cancer patients with low disease burden and excluded patients who showed positive findings for tumor recurrence on clinical imaging. The results of the study reported the potential use of [11C]choline PET/CT for the early restaging of hormone-sensitive prostate cancer cases after radical prostatectomy.(83) In prostate cancer cells, upregulation of choline kinase enzyme occurs, resulting in increased synthesis of PC. [11C]CHO is limited by its incapacity to distinguish tumor uptake from benign prostatic hyperplasia resulting in its limited role in primary disease. Both [11C]CHO and [18F]CHO are commonly used in the detection of biochemically recurrent prostate cancer.(84) The FDA gave its approval for the use of [11C]CHO in the evaluation of biochemically recurrent prostate cancer in September 2012. Several meta-analytical studies with [11C]CHO and [18F]CHO revealed high specificity as well as sensitivity in those patients.(85,86)
The [11C]acetate ([11C]ACE) (40) radiotracer was proposed as a tumor imaging agent in 2003.(87) Acetate is easily activated to acetyl-CoA in the cytosol and mitochondria in the presence of acetyl-CoA synthetase. For the cholesterol and fatty acid synthesis, acetyl-CoA acts as a common metabolite, which is then integrated into the membranes.(88) While in tumor cells, the majority of acetate is rapidly converted into fatty acids by fatty acid synthetase, which is highly expressed in tumors.(89) Initially, [11C]ACE was applied in cardiology and neurology but not in oncology for the measurement of oxidative metabolism in the myocardium and in vivo study of glial–neuronal interactions in the brain.(90,91) [11C]ACE is proved as a PET imaging agent in different tumors like prostate, liver, and others.(92−94) In the cells of prostate cancer, the surplus amount of fatty acid synthase enzyme present is involved in the conversion of acetate to fatty acid (FA) used in the production of PC.(84) [11C]ACE not only helps in the detection of advanced prostate cancer but also helps in the evaluation of localized disease. The Mena group conducted a study on 39 subjects with localized disease and found a higher uptake in tumors compared to the normal prostate tissue.(95) Due to the low sensitivity (75%) and low specificity (76%) of [11C]ACE in the detection of the primary tumor, it cannot be used independently for imaging primary prostate cancer.(96) [11C]ACE PET imaging can be an effective method for the early stage detection of prostate cancer recurrence after radical prostatectomy. Earlier, there were no methods or reference standards to detect tumor growth in the pelvic region. Many groups got positive results representing cancer cell activity in the tumor locations, indicating prostate cancer recurrence, and a correlation between recurrence and SUV value with the initial Gleason score in prostate cancer patients.(97−100) [11C]ACE showed 90% sensitivity in the detection of HGG compared to 100% sensitivity of 11C-MET.(101) [11C]acetate also showed good efficiency in differentiating HGG and LGG(102) and also between grade IV and III gliomas.(103) However, it did not show promising results in tumor grading of meningioma.

2.3. DNA Synthesis

[11C]Thymidine (substrate for TK-1 in DNA synthesis) (37) was synthesized as a PET imaging agent for measurement of the proliferation rate of cells.(104) Proliferative activity of cells is one of the hallmarks of malignant cells. [11C]Thymidine is the first radiotracer to successfully study the proliferative activity in various tumors.(105) The rapid and complex in vivo metabolism of the tracer and the resulting demands on the construction of corresponding input functions made [11C]thymidine unsuitable for routine PET scanning.(106)FMAU (38), a pyrimidine analogue radiolabeled with carbon-11, was shown to be useful for tumor cell proliferation imaging.(107−109) Although [11C]thymidine gets easily incorporated into DNA, it also gets catabolized by thymidine phosphorylase, thus complicating the process of image analysis. 4′-[Methyl-11C]thiothymidine ([11C]4DST) (39), a derivative of thymidine, was developed at the National Institute of Radiological Sciences (NIRS) and was approved for clinical use.(110,111) As [11C]4DST is a nucleoside derivative, it is unable to cross the BBB. Therefore, [11C4DST accumulation in the normal brain is low. The Toyota group carried out a direct comparison of [11C]4DST and [18F]FLT patients with brain tumors. The results indicated that [18F]FLT provided better tumor visualization than [11C]4DST. Also, the results indicated similarity in the uptake pattern and values of both [11C]4DST and [18F]FLT in gliomas.(112) Tanaka et al. performed a retrospective evaluation of 11C-4DST uptake in gliomas and analyzed a correlation between Ki67 and tumor grade against 11C-MET.(113) Further, the uptake value of [11C]4DST and its comparison with [18F]FDG was carried out in several types of cancer, including head and neck cancer,(114) lung cancer,(115) multiple myelomas,(116) and renal cell cancer.(117)

2.4. Amino Acid Transport and Protein Synthesis

2.4.1. Amino Acid Transporters

Depending on the structure, amino acids (AAs) cross cell membranes via amino acid transport systems. In mammals, based on the substrate that is transported, the amino acid transport system can be classified into neutral, acidic, or basic.(118) In tumor cells, to meet the increasing demand of AAs, the expression of amino acid transporters is enhanced. Besides being the building blocks of protein, AAs are the precursors for the synthesis of nucleotides, amino sugars, and glutathione.(119) Thus, amino acid uptake and transport is more important than the rate of protein synthesis in tumor cells.(120) Different transport systems, such as system A, xCT, glutamine, and cationic amino acid transporters, have also been studied in tumor imaging with various radiolabeled amino acid PET tracers.(121−123) Among all of these systems, the l (leucine preferring)-type amino acid transport system is the most suitable transport system for glioma imaging due to its activity at the BBB.(124,125) It has four subtypes—LAT1, LAT2, LAT3, and LAT4. LAT1 is highly expressed in primary human cancers and cancer cell lines due to its importance in the growth and survival of tumor cells. High expression of LAT1 is associated with cell proliferation and angiogenesis, and it is important in cell signaling via the mTOR pathway which is involved in cell growth regulation and division.(126) LAT subtypes 1 and 2 are overexpressed in neoplastic tissues in both gliomas and brain metastases.(127−129) This makes these amino acid transporters a convincing target for PET imaging of these tumor types.(129) An l-type system is a reversible amino acid transport system;(130) tumoral effluxes of non-metabolized amino acid also occur, causing gradual washout of radioligand on dynamic PET images.(131) The system A (alanine-preferring) amino acid transporter deals with the transport of small aliphatic AAs, including serine, alanine, and glutamine. System A transports AAs with the N-methyl group.(132) Met gets incorporated into proteins, and it plays a role in transmethylation processes.(133) [1-11C] AAs have carbon-11 labeled at the alpha-carboxylate (−COOH) position. [1-11C]-Labeled natural AAs 11C-l-leucine ([11C]Leu) (41),(134)11C-l-methionine ([11C]Met) (42),(135)11C-l-phenylalanine ([11C]Phe) (43),(136) and l-[11C]tyrosine ([11C]Tyr) (44)(137) are involved in the synthesis of proteins and can be used to measure the rates of protein synthesis. [11C]Methionine gets highly accumulated in the malignant tumor cells compared with most normal tissues.(138,139) The [11C]MET (45) amino acid is one of the first amino acid tracers used.(140) Its uptake is mediated by LAT1 and has been extensively used for the detection of CNS tumors,(13,141−144) A correlation has been observed in decreased [11C]MET uptake over time post-therapy with long-term survival.(145) [11C]MET was demonstrated in detection, grading, delineation, and differentiating recurrences.(146) However, [11C]MET showed less sensitivity in studies with low-grade glioma,(13,147) Until now, there has not been much evidence about the utility of [11C]MET in tumor grading, as well as its role in differentiating tumor recurrences from radiation necrosis, which is quite controversial.(148−152) Though [11C]MET shows high sensitivity for gliomas, its use is limited because of false-positive results seen under benign conditions, such as instances of demyelination, leukoencephalitis, or abscess.(153) The diagnostic performance of MET PET is slightly lower, with an accuracy of roughly 75%,(152,154) and is most likely related to the higher affinity of MET for inflammatory processes.(155) [11C]MET is also reported as a PET tracer for prostate imaging with enhanced PSA levels.(156,157)
The ([11C]MCYS) (46), a PET tracer for tumor imaging, reportedly an analogue of 11C-MET, seemed to have potential value as a PET imaging agent for tumors.(158,159)[11C]MeAIB (47) is an N-substituted labeled non-natural amino acid that targets transport system A.(160,161) [11C]MeAIB is used for head and neck cancer imaging. Several non-natural AAs labeled at [1-11C], including [11C]ACPC (48), [11C]AIB (49), and [11C]ACBC (50), do not get integrated into protein synthesis and were used in some studies to image amino acid transport in a tumor.(162,163)[11C]5-HTP (51) is an amino acid PET tracer being successfully used in imaging neuroendocrine tumors and for the detection of early recurrence of small tumors.(164−166) This radiotracer is more sensitive to pancreatic-neuroendocrine tumors.(165) The efficient retention of [11C]5-HTP in neuroendocrine tumors is contributed by its uptake by the LAT1 transport system, decarboxylation by aromatic l-amino acid decarboxylase (AADC), and granular storage by vesicular monoamine transporters (VMATs).(167,168) [11C]Tyr (l-[1-11C-]-tyrosine), a carbon-11-labeled tyrosine kinase PET radiotracer, is used for detection and quantification in various tumor malignancies.(169−171) It enters the tumor cells via amino acid transport system l and largely gets incorporated into proteins, making it an appropriate molecular probe for rate quantification of protein synthesis. 11C-Tyr has an advantage over the [18F]FDG PET probe in cervical lymph node detection.(172)
The [11C]AMT (52) is one such example, and it has been used for imaging tumors by measuring AA’s transport rate.(173) [11C]AMT was originally developed for brain serotonin synthesis measurement,(174−177) later used in the detection of epileptogenic foci,(178−181) and currently explored in brain tumor PET imaging due to the tracer’s metabolism, which is related to tumoral immuno-resistance. AMT PET imaging uses AMT as the tracer, which is found to be accumulating in gliomas via the immunomodulatory kynurenine pathway, wherein the degradation of tryptophan causes the production of nicotinamide adenine dinucleotide (NAD+).(182) Some reports suggested the tumor immuno-resistance is due to high tumoral expression of indoleamine 2,3-dioxygenase (IDO) and the kynurenine pathway, which drew focus toward the use of AMT as a PET tracer for tumor imaging.(183,184) The results of kinetic analysis of dynamic [11C]AMT PET images provided a high accuracy in differentiating recurrent WHO grade II-1V gliomas from radiation injury.(185)
TSPO in tumor imaging: The translocator protein (TSPO) is an 18 kDa outer mitochondrial membrane protein. It is highly expressed during the process of neuroinflammation in the microglia and astrocytes.(186,187) Studies have shown upregulation of TSPO expression in astrocytic tumors, and TSPO imaging with [11C]PK11195 (53) detected the early anaplastic transformation in glioma.(188−192) The Su group used the [11C]PK11195 radiotracer and showed that dynamic PET imaging can differentiate low-grade astrocytomas from oligodendrogliomas(188) (Figure 7).

Figure 7

Figure 7. List of various target-specific carbon-11 radiotracers in oncology.

2.4.2. Cell-Based Therapy

Cell-based therapy is a rapidly emerging class of new therapeutics. Cell therapy is defined as the administration of live cell products to provide effector cells to treat disease or support other treatments. The principle of reporter gene imaging lies in the feature of imaging signals to the cells expressing the reporter gene.(193) Noninvasive molecular imaging with reporter genes is now translated into clinical imaging paradigms. However, reporter gene imaging is more confined in human subjects than in animals.(194) Trimethoprim, a highly specific small-molecule inhibitor labeled with carbon-11, was used to image genetically engineered cells required for cell-based therapy. This group synthesized 5-(3,5-dimethoxy-4 ([11C]methoxy)benzyl)pyrimidine-2,4-diamine ([11C]TMP) (54) and studied the biodistribution and sensitivity of 11C-TMP for E. coli dihydrofolate reductase (Ec dhfr) carrying cells in a xenograft mouse model. The results of the study showed that [11C]TMP rapidly accumulates in Ec dhfr carrying cells within minutes of intravenous administration. The [11C]TMP radioligand was capable of identifying less than a million xenografted cells in a small volume that is a clinically relevant number, providing advancement in current PET reporter gene technologies.(195)

3. PET Molecular Imaging Applications in Cardiology

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3.1. Oxidative Metabolism

Acetate, a two-carbon FA, is rapidly taken up by cells and converted into acetyl-CoA, which is utilized in the TCA cycle. [11C]ACE (40) was identified as an oxidative metabolism tracer.(196) The first study reported use of [11C]ACE to demonstrate the myocardial oxygen utilization in New Zealand rabbits.(197) The study also found out that, postadministration of [11C]ACE, the labeled CO2 efflux reflects myocardial oxygen consumption and it is slightly influenced by the changes in substrate utilization, i.e., <4%.(198) Another study used this tracer to study the myocardial oxidative metabolism and regional myocardial blood flow (MBF), thus determining myocardial efficiency in subjects with myocardial cardiomyopathy.(199) Another group simultaneously determined MBF and oxygen consumption with single data acquisition by using the [11C]ACE tracer.(200) The [11C]ACE radiotracer was also used to quantify the myocardial blood flow.(201) Nevertheless, the availability of [11C]ACE is limited by the short t1/2 of carbon-11 and its on-site production. Certain inorganic compounds, such as [13N]ammonia and [15O]water, are used for cardiac perfusion imaging.(202) The [15O]H2O freely diffuses into cardiomyocytes, while the uptake mechanism of [13N]NH3 is not clear. [15O]H2O is an ideal tracer for quantifying myocardial blood flow.(203)

3.2. Fatty Acid Metabolism

The myocardium requires high energy for contractile functions; hence, this energy is provided by FAs under normal conditions. Under ischemic conditions, FA oxidation is reduced, with increased glycolysis and glucose oxidation.(204) The metabolic signatures of the ischemic heart are decreased use of FAs and increased use of glucose; this feature is exploited in myocardial metabolism imaging.(205) FAs are broken down by β-oxidation in the mitochondria after getting activated to acyl-CoA. The acyl residues are further transferred into the mitochondrial matrix, the main regulatory site for FA oxidation.(206,207)[1-11C]Palmitate (55), a physiological tracer, is the first free fatty acid (FFA) introduced for imaging fatty acid metabolism of the heart(208) and can be used for evaluation of the enzymatic activity of carnitine-palmitoyl transferase I.(209) Prior studies reported that [11C]palmitate PET imaging showed the size of the defect and provided myocardial infarct quantification and its localization.(210) In an ischemic cardiomyopathic patient, the high zones of extremely depressing deposited [11C]palmitate indicated the link between cardiomyopathic state alteration in FA metabolism.(211) Myocardial ischemia, other cardiomyopathies, and cardiac tumors also show [18F]FDG uptake.(212,213)

3.3. Cardiac Neuroreceptors (β-Adrenoreceptor/β-AR)

The sympathetic adrenoreceptors β1 and β2 found on the myocardium are involved in the regulation of cardiac function. β1 receptors are richly present in normal myocardium, forming 80% of all β-receptors, but the β2-receptors are up to 50%.(214,215) The first radioligand [11C]CGP-12177 (56) is a hydrophilic, nonselective antagonist of β-receptors that had been used for cardiac PET adrenoreceptor imaging studies.(216) Because of radiochemical synthesis problems of [11C]CGP-12177, the [11C]CGP-12388 (57), an N-isopropyl derivative, was designed for clinical use.(217) The β-AR plays a vital role in heart failure, with low β-AR density being a direct indication of decreased contractility in the heart, which is an important hallmark of cardiac failure.
One research group has found that (S)-[11C]CGP-12388 could be used to detect the myocardial β-AR density and reported a greater reduction in β-AR density in idiopathic dilated cardiomyopathy.(218) [11C]CGP-12177 PET imaging can predict the cardiac function improvement in idiopathic dilated cardiomyopathy after long-term treatment with carvedilol.(219)18F-Fluorocarazolol is another tracer for the assessment of postsynaptic sympathetic neuronal functions through evaluation of β-AR density.

3.4. Myocardial Neuronal Imaging

3.4.1. Presynaptic Sympathetic Innervation

Cardiac autonomic nervous system PET imaging has been developed in the past decade, and various pre- and postsynaptic imaging agents have been used to explore the role of sympathetic dysinnervation at various stages of heart diseases.(220,221) Carbon-11-labeled meta-hydroxyephedrine ([11C]HED) (58) is a norepinephrine analogue, designed for PET imaging of sympathetic nerve terminals of the heart, and is used as an indicator of NE reuptake transporter (NET) density and synaptic NE levels.(222) A combination of fluorodeoxyglucose (FDG) viability imaging and [11C]HED imaging may prove helpful in detecting ischemic cardiomyopathy.(223) [11C]HED is a commonly used tracer for neuronal imaging of the heart. HED has a high affinity for NETs. HED myocardial retention is believed to be reliant on the continuous release as well as reuptake by NETs.(224) Studies showed an intense decrease in regional uptake of NE by sympathetic nerves with [11C]HED imaging in a pig model of hibernating myocardium.(225) [11C]HED PET imaging lacks accuracy in quantifying regional nerve densities because of rapid neuronal uptake rates. [11C]Epinephrine ([11C]EPI) (59) is a more physiological tracer, as it is continuously secreted from the adrenal medulla into the bloodstream. Although EPI is broken down by MAO, it is efficiently stored in the vesicles.(220) Hence, it is prevented from degradation, and the tracer is slowly cleared from the heart. Hence, the EPI was proved to complete flow of uptake, metabolism, and storage of neurotransmission, unlike HED where the primary target is the uptake-1 system, i.e., energy-dependent reuptake by neuronal NET without the action of metabolizing enzymes like MAO and COMT.(220)N-[11C]Guanyl-(−)-meta-octopamine ([11C]GMO) (60) has a much slower transport rate and confinement in storage vesicles.(226) The study stated the potential of [11C]GMO in the quantitative measurement of regional cardiac sympathetic nerve density and its ability to identify minimal sympathetic nerve loss. [11C]Epinephrine and [18F]fluorodopamine (a catecholamine derivative) were used to image the presynaptic sympathetic nervous system.(227,228)

3.4.2. Angiotensin II Type I Receptors (AT1-R)

PET imaging of myocardial AT1-R and CB1-R expression has grabbed attention due to its noninvasive identification of the myocardial receptors in different pathological changes that can serve as new biomarkers for cardiac risk.(229−231) The renin–angiotensin and kallikrein–kinin systems are systematically and locally functional in the myocardium.(232)[11C]KR31173 (61) was developed for visualization and quantification of myocardial AT1-R with a plan that it could provide exclusive cardiovascular prognostication in systolic heart failure patients.(233) The first study to explain the feasibility of [11C]KR31173 and PET/CT to image increased myocardial AT1-R in the myocardial infarction area was carried out in a rat model.(233) Though [11C]KR31173 and PET/CT showed good results in imaging and quantification of myocardial ATR-1 expression in both normal and abnormal conditions, further assessment and practicability of this method is necessary in different forms of heart failure.

3.4.3. Myocardial Cannabinoid Type 1 Receptor (CB1-R)

Endocannabinoids and cannabinoid (CB) receptors were primarily known for their importance in the brain function regulation, food intake, and energy balance. Their role has also been explored in the cardiovascular system.(234−236) Many studies revealed the CB1-R of endothelial cells of the coronary artery leads to causing stimulation of MAPK and spurt up reactive oxygen species and inflammation, which results in the development of atherosclerosis and cardiac dysfunction.(237) This may serve as a link between coronary endothelium function and cardiomyocytes, as well as possibly to myocardial receptor expressions.(238,239) A study showed that activation of myocardial CB1-R by endocannabinoids led to cardiac dysfunction via MAPK activation, angiotensin II receptor type 1 (AT1-R) signaling, and fibrosis.(229)[11C]OMAR (62), a specific radioligand utilized for brain PET imaging to find alterations in CB1-R such as in schizophrenia, was applied for PET imaging of the heart in the advanced obese state.(230) Due to the high lipophilicity of [11C]OMAR, it is taken up by the liver and reduces its uptake in the inferior and inferoseptal wall. This drawback of the [11C]OMAR radioligand characteristic increases the demand for a low lipophilic radiotracer with better imaging features(240) (Figure 8).

Figure 8

Figure 8. List of various target-specific carbon-11 radiotracers in cardiology.

4. PET Molecular Imaging Applications of Brain (Neurodegenerative Disorders, Addiction/Substance Abuse, Psychiatric Disorders, Epilepsy)

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4.1. Dopamine Transporters (DATs)

The dopamine transporters are sensitive to cocaine. It is a powerful addictive psychostimulant that binds to monoamine (DA, NE, and serotonin) transporter with micromolar to submicromolar affinity. Cocaine intoxication and addiction are facilitated mainly via dopaminergic pathways, with acute effects, due to inhibition of DA uptake by binding to the DAT.(241)[11C]Cocaine (63), an analogue of cocaine, binds to DAT and blocks the reuptake of DA, thereby increasing the intrasynaptic DA levels.(242) [11C]Cocaine in PET is employed to measure the density of dopaminergic neurons. Multiple PET imaging studies with [11C]cocaine demonstrated increased DAT for up to 6 weeks after the termination of cocaine use.(243,244) However, the [11C]cocaine PET imaging for measurement of dopaminergic neurons reflected no long-term changes in DAT due to cocaine use.(243) The Volkow group observed decreased uptake of tracer along with reduced distribution volume in the basal ganglia, cortex, thalamus, and cerebellum in the brain of detoxified cocaine abusers compared to controls, with no DAT changes in availability.(244,245) The β-[11C]CIT (64) PET radioligand which has specificity for DAT showed a 50% reduction of DAT availability in the striatum of Huntington’s disease (HD) patients compared to control subjects.(246)[11C]PE2I (65) showed high affinity, specificity, and selectivity binding to central DAT by displacement experiments in the monkey brain in vivo.(247) In this study, [11C]PE2I reached a peak equilibrium fast and gave a high signal-to-noise ratio in the striatal area as well as in the thalamic brain region. Results hinted at the suitability of the [11C]PE2I tracer for quantification of both striatal and substantia nigra DAT in man. Varrone et al. performed a direct comparison of quantification of the DAT in the rhesus monkey.(248) Results showed that [18F]FE-PE2I displayed faster kinetics and more metabolism than [11C]PE2I. Major limitations for clinical usage of [11C]PE2I, especially for individuals suffering from neurodegenerative disorders and movement disorders, include a long scan time as well as the need for a structural MRI for reference region definition involving an additional scan. Besides, it adds additional costs for the health care system.(249) Jonasson demonstrated [11C]PE2I data along with the SVCA extracted reference time–activity curve (TAC) could discriminate between normal controls and Parkinsonian patients suffering from degeneration of DAT availability in the putamen. Also, [11C]PE2I scans reduce radiation exposure to the patients by 70% compared to dual-scan with [18F]FDG and [123I]FP-CIT.(250) In idiopathic PD and atypical Parkinsonian disorders, unambiguous clinical diagnosis is difficult to achieve due to different degrees of alteration in the central dopaminergic and overall brain functional activity. [18F]FE-PE2I and [18F]FECNT are the two new most characterized PET tracers for DAT imaging which allowed the DAT quantification in both striatum and substantia nigra.(251)

4.2. Vesicular Monoamine Transporter Type 2 (VMAT2)

VMAT2 protein involves in the monoamines transport into synaptic vesicles. Postsynthesis of DA from l-DOPA in the nerve terminal, the neurotransmitter is transported and stored in the vesicles via VMAT2 receptors. [11C]Dihydrotetrabenazine ([11C]DTBZ) (66) showed its potential in imaging this decrease in VMAT2 receptors in PD patients.(252,253) [11C]DTBZ (selective to VMAT2) showed reduced binding in HD patients compared to controls.(254) A study showed a strong correlation between the density of striatal VMAT2 and the nonmotor symptoms of PD.(255) [11C]DTBZ and [18F]FP(+)-DTBZ are the main VMAT2 tracers. [18F]FP(+)-DTBZ targets VMAT2 receptors and is used for the diagnosis of PD.(256) Moreover, [18F]FP(+)-DTBZ provides various advantages; e.g., it is useful in the assessment of PD severity, and also, it is less affected by compensation or pharmacological regulation. Also, [18F]FP(+)-DTBZ, [18F]florbenazine, and [18F]AV-133 are VMAT2 selective and provided the protein density quantification in various clinical studies.(257−259) [11C]DTBZ is a specific VMAT2 radiotracer for PD diagnosis.(260) In comparison to [11C]DTBZ, [18F]FP(+)-DTBZ has an affinity for VMAT2 and shows lower fat solubility, providing a lesser nonspecific binding.(261) 10-(+)-[11C]DTBZ is a derivative of DTBZ, which was synthesized and evaluated via in vivo imaging for VMAT2 using micro PET study.(262)

4.3. Dopamine Receptors

Dopamine D1 receptors play an important role in schizophrenia, cognitive disorders, and PD. [11C]NNC-112 and [11C]SCH23390 are widely used in clinical studies.(263−267)[11C]NNC-112 (67) is a derivative of [11C]SCH23390; it was used in PET imaging in the zQ175 HD mouse model and wild-type mice with the diseased animals expressing less D1 receptors in the specific areas and in patients with major depressive disorder (MDD) compared with normal individuals.(268,269) The [11C]NNC-112 radioligand PET study showed a low D1 receptor binding in the ventral striatum with increased self-administration of cocaine, indicating the role of this receptor and its contribution in enhancing the risk of relapse.(270)[11C]SCH23390 (68) is a well-known potent halobenzazepine-based D1 receptorantagonist.(271) A study was performed on HD-affected patients and reported a 50% reduction in D1 receptor density in the putamen of affected subjects compared to normal volunteers.(272) A study was conducted involving a larger group, including asymptomatic, symptomatic, and diseased subjects along with healthy control subjects, to determine the rate of loss of D1 and D2 receptors in HD over a period of 40 months.(273) Another group observed a decline in BPND (nondisplaceable binding potential) in the frontal cortex, except for the striatum in BD patients, who were not under medication for 2 or more days before the scan.(274) The specificity of [11C]SCH23390 for the D1 receptor is low, thus restricting its utility as a tool to measure the receptor density in the extrastriatal sites of the brain, such as the frontal cortex which has a receptor density lesser than that in the striatum. A [11C]SCH23390 imaging study in MDD patients with anger demonstrated a 13% decline in tracer binding in the striatal region.(275)
D2 and D3 receptors are involved in PD, schizophrenia, anxiety, or drug addiction. [11C]Raclopride, [11C]FLB-457, and 18F-fallypride are D2/D3 nonselective antagonists. [11C]MNPA, [11C]NPA, or (+)-[11C]PHNO are proven to be the suitable tracers for the study and diagnosis of disorders associated with enriched dopamine levels. [11C]Raclopride (4), a benzamide analogue having moderate affinity and reversible binding, is the most commonly used PET tracer for dopamine D2 receptor imaging.(276,277) Studies to measure D2 receptors with [11C]raclopride in HD patients explained the thalamic involvement in both premanifest and manifest HD.(278) Follow-up PET imaging studies demonstrated that reduction in [11C]raclopride binding occurs progressively in HD(279−281,273) and also in the premanifest HD.(282) The [11C]raclopride PET study was performed in symptomatic and asymptomatic HD mutation carriers and healthy controls, and a positive correlation was observed.(283,284) [11C]Raclopride is a common antagonist of D2/3 receptors used for Parkinsonian patients.(285) [11C]Raclopride PET imaging has reported the role of D2 receptor binding as a biomarker, as its decrease predicts a pleasurable response to the psychostimulant drug methylphenidate in healthy nonaddicted subjects,(286) thus increasing the addictive liability of stimulants for these subjects. Nonalcoholic members with a family history of alcohol addiction have increased D2 receptor binding.(287)[11C]FLB-457 (69) is a high-affinity D2/D3 receptor PET radiotracer, which can be used to assess cortical (extrastriatal) dopamine receptors.(288−291) No differences were observed in extrastriatal D2/D3 receptor binding using [11C]FLB-457 radioligand in major depressive disorder (MDD).(292,293) A study demonstrated low D1 and D2 binding in caudate and putamen of HD patients compared to normal control by using [11C]raclopride and [11C]SCH23390 radioligands.(294)N-[11C]Methylspiperone ([11C]NMSP) (70), a D2 receptor family radioligand, showed increased Bmax in the caudate region of unmedicated bipolar disorder (BD) patients with psychosis.(295,296) In PD and Levodopa-induced dyskinesia (LID), [11C]raclopride PET imaging was the gold standard for D2/D3 receptor density examination.(297) The limitations of the [11C]raclopride are that it fails to distinguish between D2 and D3 receptors due to the relative abundance of D2 receptors over D3. Also, [11C]raclopride results have been inconclusive when PD-LID is considered.(298−301) Payer et al. demonstrated (+)-[11C]propyl-hexahydro-naphtho-oxazin ((+)-[11C]PHNO) (12) binding in the D3-rich globus pallidus of PD patients, especially those with LID.(302) These findings suggested that D3 overexpression is a feature of PD-LID, as one-third of globus pallidus DA receptors are D3(303) and also a maximum of globus pallidus (+)-[11C]PHNO signal comes from D3 in healthy subjects.(304) Payer et al. revealed that there was no D3 receptor level upregulation in PD patients with impulse control disorders (ICDs).(305) Besides, no D2 receptor level changes were noticed in ICD and non-ICD groups. The results are contrary to the findings that D2/3 receptor level changes are involved in the development of ICD in PD.
The difference measured by performing a [11C]raclopride scan followed by administration of AMPT (alpha-methyl-p-tyrosine), a tyrosine hydroxylase inhibitor, showed a reduction in the endogenous dopamine in individuals with DSM-IV cocaine dependence.(306) Decreased endogenous dopamine release in DSM-IV alcohol-dependent individuals compared with healthy controls was reported by [11C]raclopride PET scan before and after a psychostimulant challenge to measure the presynaptic dopamine release.(307)

4.4. MAO Expression

The function of the MAO enzyme is to oxidize DA in the presynaptic neuron. Chlorgyline and deprenyl are the two suicide enzyme inhibitors that block the dopamine oxidation and elevate the DA levels in the nerve terminal. Deuterium-substituted derivatives such as [11C]clorgyline (71) and l-[11C]deprenyl (72) have been used as imaging agents to determine the expression of MAO-A and MAO-B in human subjects.(308,263) [11C]Deprenyl and [11C]deprenyl-D2 (73) are the only two tracers that have been developed for MAO-B imaging.

4.5. Adenosine Receptors

Adenosine receptors (ARs) are considered as biomarkers of HD pathology because of their role in neurotransmission.(309) It works by using four G-protein-coupled receptors—A1, A2A, A2B, and A3. Dynorphinergic medium spiny neurons (MSNs) express A1 receptors which also express D1 receptors. A2A along with D2 receptors are coexpressed in enkephalinergic MSNs.(310) [11C]KF18446 (74), a xanthine-based ligand, reported a noticeable decline in the density of A2A receptor in HD patients.(311,312) [11C]KF18446 PET imaging results showed degeneration in the A2A receptor along with D1 and D2 receptors.(311)[11C]MPDX (75) is one of the most studied xanthine derivatives utilized for various studies.(313−315) [11C]MPDX was used to evaluate A1AR changes in patients with chronic diffuse axonal injury(314) and also to study the density of A1ARs in early stage PD patients.(315) Recently, A2A AR antagonists [11C]TMSX (76) and [11C]preladenant (77) have been studied.(316−318)[18F]CPFPX (78) has been widely used for the development of suitable pharmacokinetic models for cerebral A1AR quantification.(319) Other structurally related derivatives of [18F]CPFPX named CBCPM and others have also been developed and preliminary PET studies carried out.(320,321)

4.6. Phosphodiesterase 10 (PD10)

Phosphodiesterase 10 (PD10) is abundantly expressed by the MSNs and is involved in dopaminergic and glutaminergic neurotransmission. [11C]IMA-107 (79), a selective PD10 radioligand scan, was performed to look into a cohort of manifest HD subjects with further probability. The enhanced uptake was observed in motor thalamic nuclei in comparison to control subjects, indicating the role of PD10 alterations several years before the onset of HD symptoms.(322) Future studies can contribute to determining the role of PD10 PET imaging as a possible biomarker to monitor HD progression, as well as to evaluate PD-oriented treatments. Reduction in PDE10A expression in the striatum was observed in transgenic R6/1 and R6/2 mice models of HD before the development of motor impairment.(323) Carbon-11-labeled papaverine is the first PDE10A PET radiotracer radiolabeled and evaluated in 2010.(324) However, its usage is limited by low retention in the brain. [11C]TZI964B (80) radioligand studies have shown promising results(325) following which several compounds have been synthesized for 18F-labeling, as it provides several advantages over carbon-11 radiotracers. [18F]TZ19106B and [18F]TZ8110 are the two new potent compounds that have been studied.(326,327)

4.7. Synaptic Vesicle Protein 2A (SV2A)

Synaptic vesicle glycoprotein 2 (SV2) is a candidate marker for synaptic density. In rats and humans, three isoforms of SV2 are expressed, such as SV2A, SV2B, and SV2C.(328,329) The 2A isoform is extensively found in synaptic vesicles of the CNS.(330) SV2A, a transmembrane protein, is expressed ubiquitously in almost all brain synapses, situated in synaptic vesicles, and functions as a transporter regulating the exocytosis of a synaptic vesicle, or altering the function of the synapse.(331)[11C]UCB-J (81) is a suitable PET tracer for human studies.(332,333) [11C]UCB-J, an SV2A, is the first in vivo marker of synaptic density discovered.(334) The Chen group reported the reduction in synaptic density in the medial temporal lobe of AD patients in comparison with normal subjects on assessment with [11C]UCB-J PET imaging.(335) [11C]UCB-J showed a higher uptake and faster kinetics in non-human primates and rat studies.(336) One research group used this [11C]UCB-J for the first time in a PET study in an HD animal model, and more studies need to be evaluated.(337)

4.8. Glutamatergic Receptors

Alteration in the metabotropic glutamate receptor (mGluR) was noted in presymptomatic HD mice.(338)[11C]ABP-688 (82) is a selective mGluR5 antagonist; the radioligand PET imaging was performed in the Q175 mouse model of HD to perform a longitudinal study of mGluR5 receptor changes.(339) The role of mGluR5 in AD pathology and its scope as a major therapeutic target has encouraged research on its expression monitoring and receptor binding in AD models. [11C]ABP-688 radioligand PET imaging was performed in AβPP (amyloid-beta precursor protein) transgenic mice (tg-ArcSwe), and the results displayed no difference in binding in comparison to wild-type mice.(340) One research group carried out ex vivo autoradiography, biodistribution, and PET studies with [11C]ABP-688 on rats, wild-type mice, and mGluR knockout mice.(341) PET studies on rats and wild-type mice showed radioactive uptake in the mGluR5-rich regions of the brain, whereas the homogeneous distribution of radiotracer in mGluR5 knockout mice indicated the specificity of [11C]ABP-688 radiotracer toward mGluR5. One study was performed to evaluate the mGluR5 distribution volume ratio in schizophrenia patients and compare it with the healthy subjects.(342) The results showed no difference in the mGluR distribution volume ratio in the schizophrenia patients’ brains and normal subjects. However, a marked global reduction in mGluR distribution volume ratio in healthy subjects with smoking habits was noted. Treyer et al. reported decreased mGluR5 binding of [11C]ABP-688 tracer in the hippocampus and amygdala in Alzheimer’s dementia subjects’ brains.(343) This reduction in mGluR5 binding could be either due to loss of postsynaptic binding sites or adaptive processes in AD that need to be explored in further studies. Ametamey et al. studied the use of [11C]ABP-688 tracer for mGluR5 imaging in human brains.(344) Results showed the highest [11C]ABP-688 uptake in mGluR5-rich regions of the brain.

4.8.1. NMDA Receptors

The NMDA modulators are proven to be the effective ligands for the treatment of various neurological disorders, cerebral ischemia, neuropathic pain, and psychiatric illnesses, such as depression and schizophrenia.(345)[11C]Me-NBI (83) PET tracer was designed to image GluN1/GluN2B containing NMDA receptors. A recent study has shown that only the (R)-enantiomer of [11C]Me-NB1 is more potent toward NMDA receptors. In contrast, the (S)-enantiomer of [11C]Me-NB1 showed considerable binding to sigma1 receptors.(346) Activation of NMDA receptors results in the increased Ca2+ influx into cells; however, very high levels of Ca2+ lead to cell death. [11C]Me-NBI was used in live rats to evaluate the dosage and usefulness of eliprodil (NMDA Glu2B receptor blocker).(347) The results of this investigation showed that, at neuroprotective doses of eliprodil, GluN1/GluN2B NMDA receptors are fully occupied.

4.9. Opiate Receptors

There are three subtypes of opiate receptors, such as μ, δ, and κ. [11C]Diprenorphine (84), a nonselective partial agonist for the μ, δ, and κ receptors, showed low binding in the caudate and putamen of HD patients.(348) [11C]diprenorphine and [11C]buprenorphine (85) were designed for opiate receptor imaging studies with agonist and antagonist properties. [11C]GR103545 (86), a potent κ-opioid receptor agonist, GR89696, reported remarkable kinetic values.(349)[11C]Carfentanil (87) was the first tracer studied for opiate receptor imaging.(350,351) A study reported the [11C]carfentanil radioligand and showed increased μ-opioid binding in several regions of the brain of cocaine addicts for several weeks after cocaine abstinence, suggesting an association between craving and increase in μ-opioid binding.(352) The first study to detect the involvement of the endogenous opioid in cocaine dependence and craving in cocaine addicts using [11C]carfentanil PET radiotracer showed the increased binding potential of μ-opioid receptors in various brain regions, after 1–4 days since the last cocaine use by the subjects. This increased binding potential lasted after 4 weeks of substance abstinence in the frontal cortex, thalamus, caudate, and cingulate.(352,353) Variable results have been observed by researchers by using [11C]methylnaltrindole (88) (selective for the μ-opioid receptor) or [11C]diprenorphine as PET tracers to study the opioid transporter, with results either showing increased or decreased striatal binding.(354)

4.10. GABA Receptors

GABA (γ-amino-butyric acid) receptors which are widespread in the cortex interact with GABA. Two types of GABA receptors are known, GABAA and GABAB. The GABAA receptor complex consists of a central benzodiazepine (BDZ) receptor. [11C]PK-11195 (53), a tracer for the peripheral benzodiazepine receptor (PBR), binds only to activated microglia.(355) Radioligand [11C]DPA-713 (89) from the pyrazolopyrimidine class shows more affinity toward PBR compared with PK11195. [11C]Flumazenil (3) (GABAA receptor ligand) was used in amyotrophic lateral sclerosis (ALS) patients to study the correlation between loss and cortical hyperexcitability of GABAergic transmission. The results showed a widespread reduction in binding in ALS individuals compared with controls.(356,357) A group hypothesized a reduction in GABA-benzodiazepine (GABA-BDZ) receptor function in alcohol-dependent individuals. A [11C]Flumazenil PET scan was performed by them to explore the in vivo association between the BDZ receptor and midazolam.(358) [11C]Flumazenil (FMZ) is often used to monitor the GABAA receptor to understand the pathogenesis of epilepsy.(220) The GABAA α5 subtype receptor is extrasynaptic and is involved in learning, memory, and addiction. Jim and colleagues used a [11C]Ro-15-4513 (90) PET radiotracer to study this receptor subtype in humans and reported that this tracer has about 60–70% specificity toward α5-rich regions.(359)

4.11. Serotonergic System

Serotonin is produced in the dorsal raphe nucleus of the brain, which has widespread innervations in the neocortical areas. [11C]5HTP (51), which was initially synthesized to monitor serotonin metabolism, later found its utility in neuroendocrine tumor imaging. [11C]AMT (52) was reported to indirectly evaluate serotonin synthesis.(360) A postoperative 11C-AMT PET imaging study has provided knowledge about brain plasticity postcortical resection in epilepsy patients. Increased uptake of AMT has been observed in the ipsilateral lentiform nucleus compared to the contralateral side after removal of epileptic brain tissue, thus putting forth functional reorganization of cortical–striatal projections linked with increased expression of serotonin.(361) There are 14 known subtypes of the serotonin receptors.(362) Still, an enormous amount of focus is on the development of radiotracers for the serotonin receptor subtypes.(363)
The serotonin 5-hydroxytryptamine (5-HT1A) receptor is widely expressed in the cortex region of the brain.(364)[11C]WAY100635 (91), a 5-HT1A receptor antagonist, is the first radioligand used in human imaging. The [11C]WAY100635 (a 5-HT1A ligand) PET radiotracer showed reduced binding in the specific regions of the brain in nondepressed ALS patients when compared with normal subjects.(365) [11C]WAY100635 radioligand PET imaging was performed to monitor the 5-HT1A receptor binding in AD-dementia patients.(366) In patients with temporal lobe epilepsy (TLE), the [11C]WAY100635 radioligand showed a low affinity to 5-HT1A in the TLE foci.(367) To prevent in vivo metabolism of this tracer, carbon-11 was labeled in a different position and the carbonyl-[11C]desmethyl-WAY100635 (DWAY) (92) analogue was synthesized, with excellent 5-HT1A receptor binding.(368) The [11C]NMSP (93) (an irreversible antagonist) radioligand binds to the 5-HT2A receptors in the frontal cortex.(369)[11C]MDL (94) imaging demonstrated elevated binding potential in the regions of frontal, parietal, and occipital cortices of MDD patients with remittance.(370,371)
The serotonin transporter (SERT) is located on the axons and terminals of serotoninergic neurons projecting from the raphe nuclei. SERT can be considered as a more definite marker of serotonergic terminals than 5-HT1A and 5-HT2A receptors, located also at the non-serotoninergic nerve terminals.(372)(+)-[11C]McN5652 (95) has certain drawbacks, such as its properties of in vivo metabolism, nonspecific binding, and a poor signal contrast, that restrict its application. A study used the (+)-[11C]McN5652 radioligand for PET imaging to monitor the density of SERT.(373) Other radiotracers with a high selectivity for serotonin transporters are [11C]DASB (96) and [11C]MADAM (97). These tracers have shown admirable results in SERT imaging in human brains.(374,375) To monitor the SERT binding, a group conducted an [11C]DASB imaging study in AD-dementia patients and healthy volunteers and reported reduced SERT binding in the midbrain, nucleus accumbens, putamen, and thalamus.(376,377)

4.12. Kynurenine Pathway

AMT is an analogue of tryptophan (Trp). Besides being metabolized by tryptophan hydroxylase, Trp is metabolized by tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase via the kynurenine pathway in the brain. Under normal physiological conditions, kynurenine pathways do not cause the accumulation of [11C]AMT in the brain, while it has been reported that, following ischemic brain injury or immune activation, there is an enhancement of quinolinic acid (a metabolite of the kynurenine pathway) in the brain, thus indicating the importance of the pathway in disease pathogenesis. The involvement of the kynurenine pathway in tuberous and epilepsy patients has also been well established.(378) The [11C]AMT radioligand traces tryptophan metabolism via serotonin or kynurenine pathways. Out of various molecular probes, [11C]AMT is the one radiotracer that is taken up by the epileptogenic focus in the interictal state, which otherwise shows normal scans in MRI and glucose metabolism PET. Some other PET tracers that have been used to detect epileptogenic focus are flumazenil (3), [11C]PK11195 (53), [11C]diprenorphine (84), and [11C]NMPB (101), but none has been of such effect. AMT PET guides resection with a maximum specificity and sensitivity.(379) [11C]AMT is the only tracer that can be used for identification and delineation of epileptogenic focus in their interictal state.(380) Various studies have emphasized the role of [11C]AMT PET in studying the neurobehavioral features of TSC, like autism, ADHD, and cognitive impairment.(379) Several studies have reported increased uptake of AMT in different types of cortical developmental malformations in patients with focal cortical dysplasia, subependymal heterotopia, congenital perisylvian syndrome, and polymicroglia.(381,382)

4.13. Cholinergic System

Acetylcholine neurotransmitter is involved in learning, memory, and AD. The cholinergic receptors as well as the enzymes involved in the synthesis and termination are the main targets for a valid radiotracer development utilized in imaging studies. The nicotinic class of acetylcholine receptors are ligand-gated ion channels located at the transmembrane site. Nicotine acts on nicotinic-cholinergic receptors (nAChRs), which are abundantly located in the CNS, PNS, and adrenal glands. Nicotinic receptor subtype α4β2 has been shown to have the highest affinity for nicotine.(263) The [11C]nicotine (98) radioligand showed high binding in various cortical and subcortical regions, and low binding was noted in other areas. Its clinical application is limited due to the high rate of nonspecificity, as well as due to the rapid washout of the tracer. Other carbon-11-labeled derivatives such as epibatidine, a potent analgesic, which is a toxic alkaloid obtained from Ecuador poison frog, has a high specificity for nAChRs. However, due to its toxic properties, it is unsuitable for human use. Therefore, various synthetic derivatives are underway to overcome the limitations.(383) [18F]ASEM is the first reported highly specific PET imaging agent for human α-7-nAChR receptors.(384,385)
Muscarinic receptors (mAChRs) are the most frequently found postsynaptic cholinergic receptors in the brain. Several PET pharmaceuticals, such as [11C]QNB (99), [11C]TKB (100), [11C]NMPB (101), [11C]scopolamine (102), and [11C]benztropine (103), utilized to image mAChRs did not show selectivity for its receptor subtypes. These receptors showed high binding in the areas of the cortex, striatum, thalamus, and pons. [11C]NMPB showed lower muscarinic receptor binding in neocortical areas and the thalamus with normal aging, but no specific changes were observed in AD brains,(386) while [11C]NMPB imaging showed hypersensitivity of mAChRs in the frontal cortex of PD patients.(387)
Acetylcholinesterase (AChE) enzymes function by hydrolyzing Ach, in turn regulating the concentration of ACh neurotransmitter in the synapse. Physostigmine, an inhibitor of AChE, enhances the level of ACh neurotransmitters in the synapse. The [11C]phytostigmine ([11C]PHY) (104) radiotracer uptake and retention indicated the AChE enzyme activity.(388) Certain analogues of ACh, that are substrates of AChE, such as MP4A/AMP show specificity of 94% for AChE in the brain of humans.(389) Reduced uptake was reported in AD brains in all cortical areas, with temporal and occipital cortices being most severe, whereas, with preserved uptake in the basalis of Meynert, on using analogues of ACh and substrates for AChE such as [11C]MP4P (105) and [11C]MP4A (106). This observation further suggested the phenomenon of “dying back” with cholinergic impairment beginning in the cortical areas and slowly affecting the cells of the basal nuclei.(375)

4.14. Amyloid Plaques

Aβ plaques are the hallmarks of AD. Different chemical classes of amyloid tracers are available, such as thioflavin T which includes [18F]flutemetamol, [11C]PIB, and [11C]AZD2184; stilbenes including [18F]AV-45, [18F]AV-1, and [11C]SB-13; benzoxazoles including [11C]BF-227 and [18F]BF-227; and benzofurans such as [18F]AZD4694. Pittsburgh compound B (PIB), also known as [11C]6-OH-BTA-1, was prepared based on the thioflavin-T amyloid dye.(390) Another Aβ PET tracer such as [11C]A2D-2184, on clinical evaluation, showed faster kinetics in humans.(391) The most commonly used PET tracer for Aβ imaging is [11C]Pittsburgh compound B ([11C]PIB) (107), as it showed proper retention in specific regions linked with AD amyloid pathology, while fluorine-18-labeled FDDNP binds to neurofibrillary tangles (NFTs) as well.(392) The first human PET study with [11C]PIB was carried out in 2004. An increased association between [11C]PIB cortical retention and cerebral glucose metabolism determined with [18F]FDG was most prominently observed in the parietal lobes.(393) A study reported high correlation between the binding properties of [18F]florbetapir and [11C]PIB PET in AD patients, supporting the general hypothesis that these agents generally provide analogous information.(394) Another study showed similar correlations between fluorine-labeled PIB derivative [18F]flutemetamol and [11C]PIB PET in AD patients, amnestic MCI patients, as well as healthy volunteers.(395) [11C]PIB, [18F]flutemetamol, [18F]amyvid, and [18F]florbetaben have been extensively developed for amyloid imaging. Though all of these compounds display high cortical uptake in amyloid-positive patients, nonspecific white matter binding is also observed in amyloid-negative patients.(396)[11C]SB13 (108) (stilbene) reported the same regional brain distribution pattern as PIB in AD patients and healthy controls.(397)

4.15. Tau (τ) PET Imaging

Normal physiological tau maintains the stability of microtubules. Tau consists of six isoforms in the brain, with either three or four repeats denoted as 3R or 4R of the microtubule-binding domain.(398)[11C]PBB3 (109), a first-generation τ PET radiotracer, showed favorable kinetics and high affinity to the 3R/4R tau isoform combination, which is typical in AD.(399) A study has also reported that extracellular amyloid shows no correlation with cognitive status in AD.(400) Strikingly, in the same work, a correlation between the intracellular tau NFT burden with cognitive decline was noted. The above observation hinted that tau NFTs could be a viable target for AD therapy and PET imaging of AD. Additionally, tau NFTs are involved in a variety of other dementia subtypes, including FTD, PSP, and CBD. A few studies suggested the quinolines and benzimidazoles as scaffolds of interest for tau protein.(401) The quinoline scaffold [18F]THK523 showed affinity and specificity for tau over Aβ.(402,403) Other tau tracers, such as [18F]T808 and [18F]FDDNP, showed an affinity for both tau and Aβ. A group synthesized N-[11C]methyl lansoprazole (110), performed a preclinical evaluation, and confirmed the affinity for tau NFTs.(404) A group discovered three novel tau PET tracers, such as [11C]R06924963 (111), [11C]R06931643 (112), and [18F]R06958948. These tracers showed a high affinity for tau NFTs and high selectivity against Aβ plaques.(405) Due to the mixed nature of pathology, any novel tau PET tracer should mandatorily show selectivity for Aβ plaques. However, the first clinically evaluated [18F]FDDNP PET tracer showed limited uses as tau aggregates’ biomarker, though it showed a high affinity for Aβ plaques (Figure 9).

Figure 9

Figure 9. List of various target-specific carbon-11 radiotracers for brain imaging.

5. PET Molecular Imaging Applications in Neuroinflammation

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5.1. Translocator Protein (TSPO)

TSPO is an outer mitochondrial membrane protein of molecular weight 18 kDa highly expressed in activated microglia, due to a number of factors.(406−408) There are different TSPO radioligands such as (R)-[11C]PK11195 (53) with high lipophilic and low specific binding,(409) The [11C]DPA-713 (89) radioligand shows 10 times higher binding potential than (R)-[11C]PK11195(410) and [11C]PBR28 (113) with much better in vivo imaging features than (R)-[11C]PK11195. A group reported the first PET study of (R)-[11C]PK11195 and noted an increased tracer uptake in AD subjects.(411) Studies showing glial activation in mild cognitive impairment (MCI) patients preceding clinical AD have been conducted.(412) Studies conducted(413,414) using the (R)-[11C]PK11195 PET radiotracer showed reduced binding in MCI patients but increased binding in clinical AD patients. A group observed a moderate increase in [11C]PBR28 uptake in AD patients with worsening clinical representation.(415)[11C]AC-5216 (114), a second-generation TSPO radioligand, was used in the transgenic PS19 mice model of tau pathology to study AD. The results showed that the [11C]AC-5216 tracer uptake was linearly proportional to the phospho-tau immunolabeling.(416) Studies have also been conducted on alternatives to TSPO ligands using cannabinoid 2 receptor tracers, including [11C]SCH225336 (68) and [11C]A-836339 (115).(417−419)
[11C]PBR28 (aryloxyanilide ligand), a second-generation TSPO ligand, showed higher specific binding than (R)-[11C]PK11195(407) in several CNS disorders such as epilepsy, AD, and MS.(420,408,421) [11C]DPA-713 (pyrazolopyrimidineacetamide ligand), a second-generation TSPO radioligand, also showed higher specificity than the first-generation (R)-[11C]PK11195 radioligand in distinguishing lesioned brain from the healthy normal brain in a rat neurodegenerative model.(422) A group reported the [11C]DPA-713 radiotracer to accurately quantify neuroinflammation.(423) (R)-[11C]PK11195 PET imaging showed higher binding in individuals affected with Rasmussen encephalitis or focal cortical dysplasia (FCD) but not in TLE patients.(424,425) A group has explained the high TSPO in both temporal and extra-temporal regions in TLE patients.(407)
The (R)-[11C]PK11195 TSPO PET radioligand was used to image the brain of four progressive supranuclear palsy patients, and all of them showed greater binding in specific regions compared to control patients.(426) Another study on 16 PSP-Richardson syndrome patients also showed higher binding of (R)-[11C]PK11195 tracer compared to control subjects in the specific regions of the brain.(427) (R)-[11C]PK11195 studied in the brain of four corticobasal degeneration also showed increased uptake in the specific regions.(426) The first-ever study with (R)-[11C]PK11195 on frontotemporal dementia patients showed an increase in uptake in the left dorsolateral prefrontal cortex (PFC), right hippocampus, right parahippocampus, and bilateral putamen in comparison to normal subjects.(428) The second study which was performed using [11C]PBR28 in four FTD patients showed increased binding and also reported a lack of comorbid AD pathology with amyloid PET.(429) Higher regional binding was observed in HIV+ subjects (cognitively impaired and unimpaired) in comparison to healthy controls, while the highest binding was noted in patients with HIV-associated dementia using (R)-[11C]PK11195 PET.(430) The results varied in other studies. With second-generation tracers like [11C]DPA-713 or [11C]PBR28, increased regional binding was noted in virally suppressed HIV+ individuals. HIV associated dementia with [11C]DPA-713 showed higher frontal cortex binding,(431) and [11C]PBR28 also showed region-specific binding and its association with poor performance and verbal learning and memory.(432) A fully quantitative study of TSPO with [11C]PBR28 showed higher binding in TLE patients for both ipsilateral and contralateral temporal regions.(407) One case report demonstrated increased [11C]PBR28 binding in the subacute lacunar infarction.(433) Hemorrhagic stroke PET imaging of neuroinflammation is rarely studied, unlike acute or subacute stroke. One study with (R)-[11C]PK11195 showed decreased uptake in hematomas.(434) Increased TSPO binding with (R)-[11C]PK11195 was first observed in the motor cortex and associated brain regions of ALS patients;(435) the results were reproduced with second-generation TSPO radioligands as well. A therapeutic trial of [11C]PBR28 PET in ALS subjects showed no difference.(436)

5.2. Glycogen Synthase Kinase 3 (GSK-3)

It is a serine/threonine kinase consisting of isoforms GSK-3α and GSK-3β. GSK-3β is highly expressed in the neural tissue and is involved in the regulation of brain development. PF-367 (selective inhibitors of GSK-3) when tagged with carbon-11 showed a high binding signal in the brain because of high BBB penetration and considerable selectivity for GSK-3, making [11C]PF367 (116) a lead neuroimaging agent for GSK-3.(437)

5.3. Cannabinoid-2 Receptor

Cannabinoid-2 receptors are G-protein-coupled receptors and are involved in immunomodulation and endogenous response to injury.(438) A study suggested the high expression of CB2 receptor protein in Aβ plaques in AD brain tissues in comparison to healthy individuals with immunohistochemical studies.(439) Biodistribution studies in mice with [11C]MA2 (117), a radiotracer with CB2 selectivity, showed high brain uptake and good clearance.(440) The oxadiazole derivatives [11C]MA2 and [18F]MA3 and thiophene-based tracers [11C]AAT-7782 (118), [11C]AAT-015 (119), and [18F]FC0324 show high affinity toward the CB2 receptor but suboptimal selectivity over the CB1 receptor. Studies using [11C]RS-028(441) (120) and [11C]KD2(442) (121) have shown higher and specific binding on ALS spinal cord tissues compared to that from healthy controls.

5.4. Purinergic Receptors

The P2 family of receptors mediates purinergic signaling, which plays a major role in the nervous system physiology.(443) Biodistribution studies with a radioligand [11C]A-740003 (122), selective for the P2X7 receptor in healthy rats, showed low uptake.(444) Another radioligand [11C]JNJ-54173717 (123) with potent P2X7 receptor antagonist property, when used in biodistribution studies in normal rats, easily crosses the BBB and shows clearance from plasma.(445)[11C]GSK1482160 (124), [11C]A-740003, and [11C]JNJ-54173717 are the three novel PET tracers developed for P2X7. Only [11C]JNJ-54173717 showed prominent features for in vivo evaluation and will be under clinical evaluation in the future.(445) The first potential P2Y12-receptor-based PET tracer is [11C]2 which showed very low brain uptake disfavoring its use for PET scans.(446) A preliminary study with the [11C]JN5717 P2X7 radioligand in ALS patients showed no increase in uptake.(447)

5.5. Imidazoline Receptors Type-2 (I2Rs)

Imidazoline receptors (IRs), also known as imidazoline binding sites, consist of two subtypes: I1R and I2R. Though the functions of type-2 imidazoline receptors are unknown, its contribution to various CNS disorders, such as AD, PD, HD, aging, depression, and glial cell tumors, is known. [11C]FTIMD (125), an I2R PET tracer, showed region-specific binding in rat and monkey brains. However, the binding specificity was relatively low.(448,449) The [11C]BU99008 (126) PET radiotracer for I2R imaging showed high specific binding and brain penetration in porcine and rhesus monkey brain.(450,451) Currently, [11C]BU99008 PET imaging is under human clinical trial in Alzheimer’s and healthy control patients, where the preliminary studies have shown quite promising results.(452)

5.6. Monoamine Oxidase Enzyme

MAO enzyme has two subtypes, MAO-A and MAO-B, where MAO-B showed upregulation in the neuroinflammation of AD.(453) MAO-B radioligand [11C]DED (l-[11C]deprenyl-D2) (127) PET imaging studies have been performed under various neuroinflammatory conditions involving astrogliosis, such as AD(454) and ALS(455) Though studies of MAO-B PET imaging reported knowledge on astrocyte function, its expression is also observed in serotonergic and histaminergic neurons;(456) hence, the results need to be cautiously evaluated.

5.7. Cyclooxygenase (COX)

The COX-1 and COX-2 are involved in catalyzing the conversion of arachidonic acid to prostaglandin, involved in inflammatory signaling. The [11C]ketoprofen ([11C]KTP) (128) PET tracer provided the usefulness of COX-1 in a rodent study.(457) Other studies showed microglial selectivity following the injection of inflammatory agents.(458) Another radiotracer [11C]KTP-ME (129) (COX-1 radioligand) is ready for human studies.

5.8. Arachidonic Acid

It is considered as a potential imaging target for neuroinflammation, despite its nonspecific cellular localization, as it plays an important role in the neuroinflammation process.(459) Involvement of this acid metabolism was studied in the brains of AD patients, along with visual stimulation, and its involvement in neurotransmission with [11C]arachidonic acid (130) imaging studies.

5.9. Adenosine Receptors

The A2A receptor’s (A2AR) involvement in neuroinflammatory processes has been studied in various human neurological disorders, including PD and schizophrenia. The higher A2AR binding in the activated microglia(460) was observed by using the [11C]TMSX (76) radioligand for imaging secondary progressive MS patients.(461) Studies using A2AR ligands are limited by specificity issues. To assess the pathological consequences of neuroinflammation, [11C]PIB (107) PET imaging reported for Aβ plaques in human subjects has also been used to assess demyelination.(462)[11C]Flumazenil (3) radioligand targeting GABAA receptors have been used to image neuronal integrity in neurological disorders such as stroke(463) and AD(464) (Figure 10).

Figure 10

Figure 10. List of various target-specific carbon-11 radiotracers for neuroinflammation.

6. Conclusion

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Based on recent findings on various receptor targets, enzymes, and pathways, the development of various carbon-11 radiotracers used as PET imaging agents and its intriguing application in oncology, cardiology, neurology, and neuroinflammation is at a promising stage. To date, various target receptors and pathways have been identified as potential biomarkers for tumor diagnosis, prognosis, and therapy. Their application in PET imaging has been elaborated in this review with emphasis on receptor tyrosine kinases, tyrosine kinase inhibitors, membrane phospholipid phosphatidylcholine, DNA synthesis measurement, and several amino acid transporters.
In cardiology, the identified biological processes and target receptors for PET imaging include oxidative metabolism for quantification of myocardial blood flow and determination of oxygen consumption; fatty acid metabolism for ischemia; beta-adrenoreceptors which act as a hallmark of cardiac failure besides being applied in idiopathic dilated cardiomyopathies study; presynaptic sympathetic innervation explored in ischemia, heart failure and arrhythmia, and angiotensin II type 1 receptors in myocardial infarction; and cannabinoid type 1 receptors in atherosclerosis, cardiac dysfunction, and CAD. Various molecular targets have been reported in brain imaging with a focus on their applications under normal, abnormal, and diseased conditions. This review has summarized the role of these receptors, enzymes, and pathways along with its contribution in the development and enhancement of various widespread neurodegenerative and neurological disorders, such as AD, PD, HD, MS, ALS, cerebral ischemia, neuropathic pain, temporal lobe epilepsy with detailed explanation on DATs, dopamine receptors, VMAT2, adenosine receptors, PD10, SV2A, glutamatergic receptors, opiate receptors, GABA receptors, serotonergic receptors -5HT1A5HT2A, SERTs, nicotinic receptors, muscarinic receptors, AChE, beta-amyloid, tau, kynurenine pathway, and NMDA receptors along with several specific carbon-11-labeled radioligands. For various neuropsychiatric and neurobehavioral disorders including depression, schizophrenia, bipolar disorder, autism, cognitive impairment, ADHD, the value of DAT, opiate, serotonergic and NMDA receptors have been widely explored. In alcoholics, smokers, and cocaine and other substance abusers, the importance of the change in density of receptors and changes in enzymes have shown interesting results by the utilization of several carbon-11 radiotracers as imaging agents.
Currently, neuroinflammation is a hot topic of research with increasing studies on the most commonly contributing receptor TSPO, along with recently explored alternative contributors such as GSK-3β, CB2 receptors, P2, I2R, MAO-B, COX-1, arachidonic acid, and adenosine receptors. This review provides collective information on the involvement of these receptor abnormalities and changes and how various target-specific carbon-11 PET radiopharmaceuticals provide valuable interpretation in several neurological illnesses such as AD, AD with dementia, MCI, PD, HD, FCD, FTD, corticobasal degeneration, ALS, PSP, epilepsy, HIV-associated dementia, stroke, and other CNS disorders. Besides this, the pathological consequences of neuroinflammation have also been monitored with stress on the BBB, demyelination, apoptosis, and neuronal loss considering molecular imaging agents against beta-amyloid, GABAA, and others.
This review is an approach to show the contribution of all of the extensive research on PET molecular targets, such as various physiological receptors, enzymes, pathways, and processes in normal as well as disease pathogenesis and how development and more discovery of certain target-specific carbon-11-labeled radioligands can be utilized widely in the diagnosis, disease progression, prediction, and therapy of some serious medical conditions covering tumors, neurodegenerative disorders, demyelinating diseases, addiction, neuropsychiatric illnesses, and neuroinflammatory conditions and related pathologies adding burden to both the physical and mental health of both the patient and the caregiver.

Author Information

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  • Corresponding Author
  • Authors
    • Ahana Bhattacharya - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
    • Raman Kumar Joshi - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
    • Chandana Nagaraj - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
    • Rose Dawn Bharath - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, India
    • Pardeep Kumar - Department of Neuroimaging and Interventional Radiology (NIIR), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru 560 029, IndiaOrcidhttp://orcid.org/0000-0002-1832-798X
  • Author Contributions

    N.S.G., A.B.: These authors contributed equally.

  • Notes
    The authors declare no competing financial interest.

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Nerella Sridhar Goud

Nerella Sridhar Goud received his Master’s degree in Pharmaceutical Chemistry from Kakatiya University in 2014 and Ph.D. degree from the National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, in 2019. Now working as a research associate of radiochemistry at NIMHANS. His research interests include small-molecule synthesis, SAR studies, radiolabeling studies, drug discovery and development for cancer, and neuro-related diseases. He has published more than 20 research and review articles in peer-reviewed scientific journals. He is an awardee of Genius book and India book record for successfully delivering a marathon nonstop 30 h lecture on the principles of pharmaceutical chemistry.

Ahana Bhattacharya

Ahana Bhattacharya obtained her Master’s degree in Life Sciences (2016) with a specialization in Cell and Molecular Biology from Presidency University, Kolkata. During her Master’s, she worked on the identification of a common food-borne rotavirus by the PCR method. She completed her MPhil in Neurosciences (2017–2019) from NIMHANS. There she worked on the analysis of age-related protein aggregates in the ENS and brainstem under the guidance of Professor Yasha TC in the Department of Neuropathology. She secured the first position and was awarded the gold medal during her MPhil and graduation program. Currently, she is working as a research scholar in the Department of NIIR at NIMHANS. Her research interest lies in neurosciences, neurodegenerative disorders, molecular imaging, oncology, neuropathology, stem cell therapy, and molecular biology.

Raman Kumar Joshi

Raman Kumar Joshi obtained his Bachelor’s degree in Science (2008) and Master’s degree in Nuclear Medicine from Panjab University in 2015. He worked as a nuclear medicine technologist with GE Healthcare for four years. He also worked in various centers for PET and SPECT imaging modalities and gained tremendous knowledge in the field. His excels at cyclotron operation and radiolabeling of F-18, Ga-68, N-13, and Tc-99m isotopes for imaging and Re-188 and Lu-177 for the therapy. He has been working as a radiochemist at NIMHANS since July 2017. He is the member of the NIMHANS radiation safety committee. His area of interest includes medical cyclotron, radiolabeling, and troubleshooting. He has more than five publications in national and international journals.

Chandana Nagaraj

Chandana Nagaraj received her Bachelor’s degree in Medicine (MBBS) from Bangalore Medical College in 2003 and Master’s degree in Medicine-DNB (Nuclear Medicine) from Christian Medical College in 2010. She has been an associate professor at NIMHANS since 2015. She is involved in many skill development programs and teaching for the paramedical staff, technologists, radiochemists, physicists, radiographers, and students with a view to enabling them to acquire skills and expertise for continued growth and excellence in research. Her research interest mainly focuses on PET image processing techniques, sequential analysis, pharmacokinetic modeling, etc. Currently, she is handling four major clinical research projects funded by different Indian government agencies like ICMR, DST, and NIMHANS.

Rose Dawn Bharath

Rose Dawn Bharath obtained her Bachelor’s degree in Medicine (MBBS) from Kempegowda Institute of Medical Sciences in 1999 and Master’s degree in Medicine-DNB from Manipal Hospital, Bangalore, in 2003. She has completed the Doctor of Medicine (DM) course from the National Institute of Mental Health & Neurosciences (NIMHANS) in 2007. Currently, she is a professor of neuroimaging and interventional radiology with 17 years of experience in imaging techniques and 14 years of exclusive neuroimaging expertise. Apart from being a consultant neuroradiologist, she has an active research interest in the field of functional neuroimaging and currently is in charge of the DST sponsored Advanced Brain Imaging Facility at NIMHANS. She has more than 200 publications in peer-reviewed scientific journals.

Pardeep Kumar

Pardeep Kumar has obtained his Ph.D. from Panjab University, Chandigarh, and did a thesis on the development of novel radiotracers for cancer detection at the Department of Nuclear Medicine, PGIMER, Chandigarh, from 2009 to 2013. Afterward, he joined as a postdoctoral fellow at Thomas Jefferson University, Philadelphia, PA, USA, under Prof. Mathew Thakur from 2013 to 2017. He has developed gallium-68-labeled peptide for the detection of breast cancer using micro PET-CT imaging. He has joined NIMHANS as an assistant professor of radiochemistry in the Department of NIIR in 2018. His research interest involves developing radiotracers for imaging neuro disorders, chemoresistance, and gliomas.

Acknowledgments

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The authors are thankful to the National Institute of Mental Health and Neuro-Sciences & Ministry of Health & Family Welfare, Govt. of India, for providing resources and support.

Abbreviations Used
AAs

amino acids

AADC

aromatic l-amino acid decarboxylase

AβPP

amyloid beta precursor protein

ACE

angiotensin-converting enzyme

AChE

acetylcholinesterase

AD

Alzheimer’s disease

ADHD

attention deficit hyperactivity disorder

AGE

advanced glycation end product

ALS

amyotrophic lateral sclerosis

APUD

amine precursor uptake and decarboxylation

AR

adenosine receptors

AT1-RC

angiotensin II receptor type 1

BBB

blood–brain barrier

BD

bipolar disorder

BDZ

benzodiazepine

CA

carrier-added

CAD

coronary artery disease

cAMP

cyclic adenosine monophosphate

CB

cannabinoid receptor

CBD

corticobasal degeneration

CB1-R

cannabinoid type 1 receptor

cGMP

cyclic guanosine monophosphate

CNS

central nervous system

CO2

carbon dioxide

COMT

catechol-O-methyltransferase

DA

dopamine

DATs

dopamine transporters

dMCAO

distal middle cerebral artery occlusion

DMSO–DMF

dimethyl sulfoxide–dimethylformamide

EGFR

epidermal growth factor receptor

EOB

end of bombardment

EOS

end of radiosynthesis

ERP

end of radionuclide production

FA

fatty acid

FFA

free fatty acid

FMAU

2′-fluoro-5-methyl-1-β-d-arabino-furanosyluracil

FTD

frontotemporal dementia

GBq

gigabecquerel

GC

gas chromatography

HD

Huntington’s disease

HER2

human epidermal growth factor receptor 2

HGG

high-grade glioma

HPLC

high-performance liquid chromatography

5-HTP

5-hydroxytryptophan

IDO

indole amine 2,3-dioxygenase

LAH

lithium aluminum hydride

LAL

limulus amebocyte lysate

LAT

l-type amino acid transporter

LGG

low-grade glioma

mAChRs

muscarinic receptors

MAGL

monoacylglycerol lipase

MAO

monoamine oxidase

MAPK

mitogen-activated protein kinase

MBF

myocardial blood flow

MBq

megabecquerel

MCI

mild cognitive impairment

mCi

millicurie

MDD

major depressive disorder

mGluR

metabotropic glutamate receptor

MS

multiple sclerosis

MSNs

medium spiny neurons

nAChRs

nicotinic-cholinergic receptors

NCA

no-carrier-added

NE

norepinephrine

NET

NE reuptake transporter

NMDA

N-methyl-d-aspartate

NSCLC

non-small-cell lung carcinoma

PC

phosphatidylcholine

PD

Parkinson’s disease

PET

positron emission tomography

PFC

prefrontal cortex

PNS

peripheral nervous system

PSP

progressive supranuclear palsy

RT

room temperature

RTKs

receptor tyrosine kinase

SERT

serotonin transporter

TBAH

tetrabutylammonium hydroxide

TBR

tumor-to-background ratio

TCA

tricarboxylic acid

TEA

triethylamine

TK-1

thymidine kinase-1

TKI

tyrosine kinase inhibitors

TLC

thin layer chromatography

TLE

temporal lobe epilepsy

TMAO

trimethylamine N-oxide

TMP

thymidine monophosphate

TSPO

translocator protein

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

VMAT2

vesicular monoamine transporter type 2

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Cited By


This article is cited by 1 publications.

  1. Rubel Chakravarty, Sudipta Chakraborty. Production of a broad palette of positron emitting radioisotopes using a low-energy cyclotron: Towards a new success story in cancer imaging?. Applied Radiation and Isotopes 2021, 176 , 109860. https://doi.org/10.1016/j.apradiso.2021.109860OpenURL HONG KONG UNIV SCIENCE TECHLGY
  • Abstract

    Figure 1

    Figure 1. Commonly used PET radiotracers for diagnosis under various clinical conditions.

    Figure 2

    Figure 2. Cyclotron production and β+-decay process of carbon-11 radionuclide.

    Figure 3

    Figure 3. Transformation of different precursors from carbon-11 radionuclide.

    Figure 4

    Figure 4. Reaction pathways for [11C]CO2 fixation into urea, carbamates, oxazolidinones, carboxylic acids, amides, and their carbon-11 radiotracer derivatives.

    Figure 5

    Figure 5. Reaction pathways for generation of secondary precursors and their carbon-11 radiotracer derivatives.

    Figure 6

    Figure 6. Carbon-11 radiotracers through C–C bond formation from various well-known reaction mechanisms.

    Figure 7

    Figure 7. List of various target-specific carbon-11 radiotracers in oncology.

    Figure 8

    Figure 8. List of various target-specific carbon-11 radiotracers in cardiology.

    Figure 9

    Figure 9. List of various target-specific carbon-11 radiotracers for brain imaging.

    Figure 10

    Figure 10. List of various target-specific carbon-11 radiotracers for neuroinflammation.

  • References

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